38 - Diabetic and atherosclerosis-prone rats have sex-specific severe dyslipidemia, associated with serum lipid oxidation

Abstract

Cardiovascular disease and atherosclerosis are devastating diseases in the modern world. Diabetes is a common comorbidity that accelerates progression of atherosclerosis. There is much need for a small animal model to recapitulate the human condition. Serum biomarkers are useful to confirm disease diagnosis, monitor progression and prognosis. We knocked-out apoE using CRISPR-Cas9 in the Zucker Diabetic Fatty(ZDF) rat to develop the first obese, dyslipidemic, atherosclerotic and diabetes-prone(apoE-/-;ZDF) rat. Our hypothesis is that our mutant rats have increased serum-lipid oxidation levels compared to non-obese, non-diabetic rats with a difference in sex, diet and onset of obesity and diabetes. Methods Female/male adult apoE-/-; ZDF and apoE-/-; LZ(dyslipidemic, non-obese, non-diabetic) rats were placed on normal or high fat diet at 3 months of age for 3 months with weekly weights and food intake assessment. Serum was isolated at 3 and 6 months of age via tail vein. Total cholesterol, LDL and glucose levels were analyzed. TBARS MDA assay to study lipid oxidation was performed following manufacturer’s protocol. Results Serum analysis evidenced higher than normal total cholesterol, LDL and MDA levels at 3 months of age in all rats. Diabetic rats evidenced higher levels of body weight, serum glucose, lipids and MDA compared to non-diabetics. Lipid levels increased significantly after 3 months in high fat diet fed-rats compared to normal chow. Obese-diabetic females develop more severe dyslipidemia (~3 fold) but lower weight amd glycemia compared to obese-diabetic males. Simple linear regression was calculated to predict MDA concentration based on Total cholesterol (F(1,32):40.48, p Conclusion There is sufficient evidence to support the relationship between lipid levels and lipid oxidation in our rat model. However, unexpectedly there was no correlation with glycemia. There is a marked difference in disease development marked by sex and diet implementation, future studies will study such differences. Supported by:NORC-PPF(P30 DK056350) to EMB.